It is proposed to characterize the genes and gene products required for developmentally regulated nuclear migrations in photoreceptors of the Drosophila compound eye. Nuclear migration is of universal importance in animal development. For example, the human brain disorder, Lissencephaly, is the result of neural nuclei failing to migrate appropriately during brain development. Moreover, the Drosophila homolog of the human Lissencephaly gene, Lis1, is essential for photoreceptor nuclear migrations in Drosophila. Thus, the genes and proteins that will be identified and studied are directly relevant to human development and disease. Nuclear migration is an important phenomenon to understand also because of its relationship to other critical processes in eukaryotic development. Many of the proteins important for nuclear migration are also required for the transport of other organelles, establishment of cell polarity, and morphogen localization within the cell. There are four specific goals of the research proposed. The first is a structure/function analysis of Klarsicht, a protein required for photoreceptor nuclear migration. Transgenic flies expressing partial Klarsicht proteins will be used to correlate subcellular localization, protein binding, and organelle migration functions with protein structure. The second aim is to clone and characterize the egk1 gene, which like klarsicht, is essential for photoreceptor nuclear migration. Thirdly, antibodies to a variety of proteins will be used to order four nuclear migration genes, klarsicht, egk1, BicD and DLis-1, into a pathway. In addition, the possibility of physical interactions between Klarsicht and Egk1 proteins will be explored using in vivo and in vitro assays. Finally, a variety of different genetic screening approaches will be used to identify additional genes in the klarsicht/egk1 pathway.